Physician Conformity and Patient Adherence to ACE Inhibitors and ARBs in Patients With Diabetes, With and Without Renal Disease and Hypertension, in a Medicaid Managed Care Organization

BACKGROUND: The American Diabetes Association (ADA) recommends using angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with diabetes and comorbid hypertension or renal disease. OBJECTIVES: To examine the use of ACE inhibitors and ARBs in members of a Medicaid managed care organization (MCO) with diabetes and a diagnosis of hypertension and/or kidney disease to determine to what extent (1) physicians are conforming to the recommended course of treatment according to ADA guidelines published in 2002 and still current and (2) patients are adhering to their prescribed therapy. METHODS: Patients with diabetes were identified using medical claims from a Medicaid MCO in Maryland of approximately 118,000 members continuously enrolled during the study period. To be included in the cohort, members had to have at least 1 medical claim containing a diagnosis of diabetes mellitus from April 1, 2001, through March 31, 2002, using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code of 250.xx. Additional medical claims during the same time period for hypertension, ICD-9- CM code 401.xx, and renal disease, ICD-9-CM codes for nephropathy (582.81 or 582.9), proteinuria (791.0), or diabetic nephropathy (250.40 or 250.42 for type 2 diabetes only), were used to categorize the cohort into 4 subgroups: diabetes and renal disease with hypertension, diabetes and renal disease without hypertension, diabetes and hypertension without renal disease, and diabetes without renal disease and without hypertension. Pharmacy claims for ACE inhibitors and ARBs were obtained from July 1, 2001, through June 30, 2002, and utilization was defined as the patient having at least 1 pharmacy claim for an ACE inhibitor or an ARB. Patient adherence with ACE inhibitor or ARB therapy was measured using medication possession ratio (MPR) and median gap between prescription refills. RESULTS: There were 1,698 patients, approximately 2.3% of the total continuously enrolled members, with 1 or more medical claims containing an ICD-9-CM code of 250.xx for diabetes mellitus. The average age was 48 ± 13.2 years for the total sample, and nearly 70% of the patients were women (1,188 women and 510 men). Only 13% of the patients in the sample had medical claim evidence of any renal involvement, while 63% of the study patients had hypertension. A total of 915 patients (53.9%) had at least 1 pharmacy claim for an ACE inhibitor or an ARB, accounting for 7,934 unique pharmacy claims, an average of 8.7 pharmacy claims per patient. Patients with renal involvement and without hypertension (47%) were less likely to receive an ACE inhibitor or an ARB than patients with renal involvement and hypertension (85%) (P less than0.001). Patients without renal involvement or hypertension (19%) were less likely to receive an ACE inhibitor or an ARB than patients with hypertension and no renal involvement (71%) (P less than0.001). The MPR for all patients was 0.77 (± 0.26). MPR and median gap did not differ significantly by sex. However, we found a significant correlation between age and MPR (P less than0.001). In this sample with an age range of 18 to 65 years, there was a positive relationship between patient age and adherence to ACE inhibitor or ARB therapy. CONCLUSIONS: Physicians' conformity is high when they prescribe an ACE inhibitor or ARB for patients with diabetes and hypertension but is lower than expected for patients with diabetes and renal disease but without hypertension. Older patients in this analysis of persons aged 18 to 65 years adhered more to their ACE inhibitor or ARB therapy.

RESULTS: There were 1,698 patients, approximately 2.3% of the total continuously enrolled members, with 1 or more medical claims containing an ICD-9-CM code of 250.xx for diabetes mellitus. The average age was 48 ± 13.2 years for the total sample, and nearly 70% of the patients were women (1,188 women and 510 men). Only 13% of the patients in the sample had medical claim evidence of any renal involvement, while 63% of the study patients had hypertension. A total of 915 patients (53.9%) had at least 1 pharmacy claim for an ACE inhibitor or an ARB, accounting for 7,934 unique pharmacy claims, an average of 8.7 pharmacy claims per patient. Patients with renal involvement and without hypertension (47%) were less likely to receive an ACE inhibitor or an ARB than patients with renal involvement and hypertension (85%) (P <0.001). Patients without renal involvement or hypertension (19%) were less likely to receive an ACE inhibitor or an ARB than patients with hypertension and no renal involvement (71%) (P <0.001). The MPR for all patients was 0.77 (± 0.26). MPR and median gap did not differ significantly by sex. However, we found a significant correlation between age and MPR (P <0.001). In this sample with an age range of 18 to 65 years, there was a positive relationship between patient age and adherence to ACE inhibitor or ARB therapy. CONCLUSIONS: Physicians' conformity is high when they prescribe an ACE inhibitor or ARB for patients with diabetes and hypertension but is lower than expected for patients with diabetes and renal disease but without hypertension. Older patients in this analysis of persons aged 18 to 65 years adhered more to their ACE inhibitor or ARB therapy. ramipril significantly reduced the risk of a composite outcome of sudden death and resuscitated cardiac arrest by 21% compared with placebo (P = 0.028) in patients without systolic dysfunction. 7 Many clinical studies have shown that ACE inhibitors decrease the risk of adverse outcomes, including macrovascular and microvascular complications, in patients with diabetes and hypertension. [2][3][4]7 Thus, according to the ADA, ACE inhibitors are first-line therapy for most patients with diabetes and hypertension. 2,3 ACE inhibitors and angiotensin receptor blockers (ARBs) decrease the progression of albuminuria and nephropathy and therefore are considered first-line therapy for the prevention and progression of nephropathy. 9,10 Both the 2002 and 2004 ADA guidelines state, "In the treatment of albuminuria/ nephropathy, both ACE inhibitors and ARBs can be used." 9,10 Some clinicians are concerned with the potential adverse effects on renal function of patients with renal disease using an ACE inhibitor or an ARB. However, HOPE trial researchers concluded that ACE inhibitors reduce the risk of cardiovascular disease in patients with mild renal insufficiency (defined as baseline serum creatinine <2.3 mg/dl) and should not be withheld because of a moderate increase in serum creatinine. 8 Although ACE inhibitors are considered first line for the management of diabetes in patients with comorbid hypertension and nephropathy, they may not be tolerated. In a study of patients with diabetes and hypertension, the reported prevalence of cough associated with use of ACE inhibitors was 14.9%, with 4.7% of patients interrupting treatment as a result. 11 Similarly, the UKPDS Group noted that 4% of patients receiving captopril discontinued therapy due to cough. 5 ARBs are considered appropriate agents if patients cannot tolerate an ACE inhibitor. 9,10 Study Objectives This study examined the utilization of ACE inhibitors and ARBs in members of a Medicaid managed care organization (MCO) with diabetes with and without a diagnosis of hypertension and/or kidney disease to determine whether physicians are conforming to the recommended course of treatment in published guidelines and whether patients are adhering to their prescribed therapy.
ss Methods

Study Design and Participants
Pharmacy and medical claims databases from a Medicaid MCO in Maryland were obtained and used to identify the study cohort. The Medicaid MCO was founded in 1997 as a partnership between a large university-based health system and federally qualified health centers, and serves as one of the MCOs for HealthChoice, Maryland' s statewide mandatory managed care program. The Medicaid MCO had approximately 118,000 members during the study period from March 1, 2001, through June 30, 2002. As part of the pharmacy benefit through the Medicaid MCO, members had no copayment for prescriptions. The pharmacy benefit had no mail-service option, and prescription quantities were limited to a 30-day supply.
The study sample included members aged 18 to 65 years who were continuously enrolled during the study period, with medical and pharmacy coverage. Continuous medical and pharmacy coverage was defined as no gap in coverage of more than 30 days.
Patients were included in the study cohort if they had at least 1 medical claim for diabetes mellitus using the International  renal disease and without hypertension ( Figure 1). The dataset for pharmacy claims with dates of service from July 1, 2001, through June 30, 2002, contained the following fields: unique deidentified patient number, patient age (as of July 1, 2001), patient sex, prescription number, date filled, drug name, drug strength, new or refill status, MCO paid quantity, and number of paid days supplied. All data conformed to Health Insurance Portability and Accountability Act patient privacy standards, and the dataset was delivered to the researchers with deidentified patient information. The University of Maryland Institutional Review Board assigned exempt status to the research protocol.

Pharmacy Claims Analysis
Using the pharmacy claims for ACE inhibitors and ARBs for the cohort for dates of service from July 1, 2001, through June 30, 2002, patients were categorized by their first dispensed prescription into either ACE inhibitor, ARB, or combination product. Utilization was defined as the member having at least 1 pharmacy claim for an ACE inhibitor or an ARB during the study period. Patient adherence with ACE inhibitor or ARB therapy was measured using medication possession ratio (MPR) and median gap between prescription refills.
For all adherence evaluations, ACE inhibitors or ARBs were considered together. If a patient was switched from an ACE inhibitor to an ARB or vice versa, days supply for both the ACE inhibitor and ARB were summed. Days supply for the first therapy was truncated to equal the number of days from the last dispensed fill of that medication to the start of the new drug product. For patients who had an ACE inhibitor or ARB added to their existing ARB or ACE inhibitor therapy, respectively, patient adherence measures were considered only for the initial drug.
In this study, MPR was calculated by adding the total days supply for all ACE inhibitor or ARB pharmacy claims and dividing by the total possible days supply of ACE inhibitor or ARB from the date when the prescription was originally dispensed. The denominator of total possible days supply consisted of the number of days from the first fill until the end of the study period to account for prescriptions filled later in the study period. We chose to truncate the MPR at 1.0 to prevent overestimation of MPR (e.g., last fill greater than the days supply remaining in the evaluation period). Patients were categorized, based on their MPR, into 3 categories: "Good" (MPR ≥0.8), "Poor" (MPR 0.5-<0.8) and "Very Poor" (MPR <0.5).
The median gap of time in days between ACE inhibitor or ARB prescription refills is another measure of patient adherence. The median gap in this study was calculated as the median of the number of days a prescription was refilled in relation to the end of the days supply of the previous prescription. A positive median gap represents the number of days the member was late in filling subsequent refills, with larger numbers denoting lower adherence.
Statistical analysis included calculations of means and standard deviations (SDs) for continuous variables. Unpaired t tests and the χ 2 statistic were used for univariate analysis of differences in demographic characteristics and adherence measures between groups. The correlation coefficient, Pearson r, was used to analyze the relationship between adherence measures and age. Statistical significance was set at an accepted alpha of P <0.05. Statistical analysis was performed with Minitab Statistical Software (Minitab, Release 13, Minitab, Inc., State College, Pennsylvania).
ss Results

Member Demographics
The study sample included a total of 1,698 members with diabetes mellitus, approximately 2.3% of total continuously enrolled members. The average age was 48 ± 13.2 years for the total sample, and nearly 70% of the patients were women (n = 1,188 women and n = 510 men). Seventy-seven percent of these patients were taking antihyperglycemic agents, including insulin and oral hypoglycemic agents. As defined by ICD-9-CM codes, only 13% of the sample had any renal involvement while 63% of the study sample had hypertension ( Figure 1).

ACE Inhibitor or ARB Utilization
Of the 1,698 patients with diabetes mellitus, 915 (53.9%) had at least 1 pharmacy claim for an ACE inhibitor or an ARB, accounting for 7,934 unique pharmacy claims during the study period (Table 1). Patients with a pharmacy claim for an ACE inhibitor or ARB each had an average of 8.7 pharmacy claims (± 5.0 SD) with an average days supply per pharmacy claim of 29.4 (± 2.4) days. Patients had an average days supply of 279 (± 108 SD) days, out of the 365-day study period (Table 1). A majority, 781 (85.4%) patients, with a pharmacy claim for an ACE inhibitor or an ARB received an ACE inhibitor, either as a single entity or combination product (Table 2). Lisinopril, as a single-entity product, was the most common ACE inhibitor dispensed in this study for almost half of all patients (49.5%) and nearly two thirds of all patients receiving a single-entity ACE inhibitor product (64.1%). Only 14.6% of patients who received an ACE inhibitor or an ARB were dispensed an ARB, either as a single entity or combination product, with losartan and irbesartan most frequently dispensed ( Table 2). (Please note that this Medicaid MCO has a formulary, which explains the high percentage of specific ACE inhibitor and ARB drugs used. However, patients receiving other agents may have been granted exceptions to receive nonpreferred agents.) A majority, 736 (80.4%) members, received the same ACE inhibitor or ARB agent as their initial prescription for all of their refills during the study period, including 57 members who had only 1 prescription filled during the study period.

Patient Characteristics and Key Findings
Utilization of ACE inhibitors or ARBs in patients with disease indications for drug therapy of hypertension and/or renal disease was calculated to be 72.6%. Only 18.5% of patients with diabetes without either of these indications were receiving an ACE inhibitor or an ARB. There were no significant differences in utilization based on age or sex. ACE inhibitors or ARBs were used in 73.5% of diabetes patients with hypertension and 78.6% of diabetes patients with renal disease. Presence of hypertension was a significant predictor for members both with and without renal disease to receive an ACE inhibitor or an ARB (P <0.001). Patients with renal involvement and without hypertension (47%) were less likely to receive an ACE inhibitor or an ARB than members with renal involvement and hypertension (85%) (P <0.001). Patients without renal involvement or hypertension (19%) were less likely to receive an ACE inhibitor or an ARB than members with hypertension and no renal involvement (71%) (P <0.001). In patients without hypertension, renal disease was a significant predictor of ACE inhibitor or ARB use (P <0.001).

Medication Possession Ratio
The average MPR for all patients was 0.77 (± 0.26) (median = 0.88), with a range of 0.08 to 1.0 (Table 3). A majority of patients (60.4%) had "good" adherence to therapy, with an MPR ≥0.8. However, 21.9% of members had "poor" adherence, with MPR ranging from 0.5 to <0.8, and 17.7% had "very poor" adherence, with an MPR of less than 0.5. MPR did not differ significantly by sex, with male members having an MPR of 0.78 (± 0.26) and female members having an MPR of 0.77 (± 0.26) (Student t test). However, we found a significant positive correlation (r 2 = 0.021) between age in the range of 18 to 65 years and MPR (P <0.001).

Median Gap between Prescription Refills
The median gap in days between prescription refills for a given patient is another method of measuring adherence with prescribed therapy. The overall mean of the median gap for patients was 7.9 (± 25.6 SD) days (Table 3). No significant difference in mean gap by sex was detected, with male members having a mean gap of 8.6 (± 27.0) days and female members having a mean gap of 7.6 (± 25.0 SD) days (Student t test). In addition, there was no significant difference in the median gap by age (Pearson r). ss

Discussion
Approximately 54% of all members with diabetes were prescribed an ACE inhibitor or an ARB in this sample cohort from a Medicaid MCO population. Most of the patients who received ACE inhibitors or ARBs in our sample were women (69.0%) between 45 and 64 years of age (73.8%).
The proportion of ACE inhibitor use was 85.4%, while ARB use was 14.6%. Examining those members with concomitant hypertension and diabetes, we found a 73.5% prescription rate for ACE inhibitors or ARBs, which is higher than in previously reported studies during the same time period. A similar patient population of Tennessee MCO members had only a 46.2% prescription rate for ACE inhibitors in patients with type 2 diabetes and hypertension in the year 2000. 12 In a study in Bahrain the same year, approximately 40% of patients with diabetes and hypertension (as determined from pharmacy claims without medical claims) seen by family physicians were receiving ACE inhibitors. 13 A more recent study using data from 2003 found a similar utilization rate to our study-the authors analyzed pharmacy claims from members of a commercial MCO with diabetes and hypertension and found a 71.6% utilization rate for ACE inhibitors or ARBs. 14 We used several measures to proxy physician conformity to existing physician practice guidelines in place during the study period and patient adherence with the prescribed ACE inhibitor or ARB therapy. In our sample, 85% of members with renal involvement and hypertension and 71% of members with hypertension (without renal involvement) were prescribed ACE inhibitor or ARB medications. According to the ADA practice guideline in place at the time of the study, which is still current today, it is recommended that patients with a diastolic blood pressure of >80 mmHg and a systolic blood pressure of >130 mmHg be treated ( Figure 2). 2, 3 We used the ICD-9-CM codes for hypertension to identify patients with diabetes and hypertension who should receive treatment. Overall, 73.5% of members (788 of 1072, Figure 1) with diabetes and hypertension in our sample were prescribed ACE inhibitor or ARB medications.
Similarly, for patients with diabetes and renal disease, there was an overall utilization rate of ACE inhibitors or ARBs of 78.6% (169 of 215, Figure 1). The 2002 and 2004 (most recent) ADA guidelines specifically address diabetic nephropathy and recommend the use of ACE inhibitors or ARBs for patients with diabetes and albuminuria/nephropathy. 9,10 These rates show high physician conformity with the evidence found in the medical literature for patients with diabetes and comorbid renal disease or hypertension. 15 Overall, 72.6% of members (806 of 1,110) with disease indications appropriate for ACE inhibitor/ARB therapy had at least 1 pharmacy claim for these agents. The largest discrepancy appeared in patients with diabetes with renal disease but without hypertension, in whom there was 47.4% use of an ACE inhibitor or an ARB (18 of 38). However, these 20 patients with renal disease but without hypertension and not receiving either an ACE inhibitor or an ARB represented only 1.2% of the sample cohort in this study.

Physician Conformity and Patient Adherence to ACE Inhibitors and ARBs in Patients With Diabetes, With and Without Renal Disease and Hypertension, in a Medicaid Managed Care Organization
MPR can be an indirect measure of physician conformity with existing practice guidelines as well as a direct measure of patient adherence with therapy. A majority (60.4%) of members had MPR rates that can be classified as "good" (≥0.8). Our 60.4% rate of adherence was lower than the rate from Wannemacher et al. 16 (77%), but that could be because of the difference in how MPR was calculated and our decision to truncate the MPR at 1.0 for individual patients as well as the difference in drugs studied. Our study was limited to ACE inhibitors and ARBs only (combined with other agents), while Wannemacher et al. also evaluated other antihypertensives, including beta-blockers, calcium channel blockers, diuretics, and a miscellaneous class (used as single agents).
In our sample, older patients (within the age range of 18 to 65 years in the study) tended to adhere more to ACE inhibitor or ARB therapy, as evidenced by higher MPRs. Patient adherence with therapy was also measured by median gap and, on average, patents were more than a week late refilling their next ACE inhibitor or ARB prescription.
Grant et al. 17 reported high patient compliance for taking all diabetes-related medicine at 6.7 (± 1.1) out of the previous 7 days. In addition, patients in their sample reported the highest 7-day adherence for agents related to the treatment of hypertension and hyperlipidemia (6.8 of 7 days for both). 17 Grant et al. were further able to tie patient adherence to perception of the medications' ability to improve their symptoms and protect their future health. They concluded that "patients' perceptions of the immediate and future benefit of prescribed medications have a significant impact on their adherence." 16 While self-reported adherence and persistence may be overestimated, Grant et al. were able to show the important role that patient comprehension of the value of treatment plays in compliance with therapy.

Limitations
The results of this study should be interpreted with some caution because of certain limitations in the dataset and in the methodology. First and foremost, we measured adherence but required as little as 1 pharmacy claim as an inclusion criterion for the study. Second, this study used data from 2001 and 2002 and, although recommendations for ACE inhibitor and ARB use have not changed, the use may be different in future years. Third, we might have missed some patients with renal disease based on the ICD-9-CM code of 585, chronic renal failure, which was not part of the inclusion criteria.
Lastly, our methods relied heavily on ICD-9-CM coding, first, in identifying patients with diabetes mellitus to define the study population and second, in defining patients with renal involvement and hypertension. This point has several implications: (1) we did not require patients to have multiple medical claims for any of the medical diagnoses (i.e., diabetes, hypertension, renal disease) or concomitant antihyperglycemic agents, so false-positive classification was possible, (2) we did not classify patients based on diagnoses at the beginning of the study period, creating the possibility that the classification of some patients did not reflect their condition during the entire study period, and (3) as with all medical claims, we had no way to evaluate the accuracy of the coding, which might have been incomplete. There are many reasons medical claims coding might be inaccurate or incomplete, including accidental or intentional miscoding.
Physician prescribing of ACE inhibitors or ARBs was determined from administrative claims. Administrative claims data do not reveal what drugs might have been prescribed but not dispensed or if the dispensed drug was actually used by the patient. Patients who had discontinued therapy before the study period because of intolerance or for other reasons would have underestimated appropriate ACE inhibitor/ARB prescribing. In addition, the adherence parameters could have been affected by the use of drug samples obtained from physician offices, which would result in underestimates of adherence. In our population, we believe sample use to be low because physicians tend to reserve samples for patients without pharmacy benefits or poor insurance coverage. This Medicaid population had broad coverage of ACE inhibitors and ARBs and no copayment.
The pharmacy claims in our study were limited to ACE inhibitors and ARBs prescribed either as a single agent or in combination with another agent, such as a diuretic or a calcium channel blocker. For this reason, previous published studies evaluating all antihypertensive medication might not be comparable.

ss Conclusion
Physicians' conformity was high when they prescribed an ACE inhibitor or an ARB for patients with diabetes and hypertension, which was expected on the basis of the medical evidence available in 2001-2002 during the study period. However, physicians' conformity was lower than expected among patients with diabetes and renal disease but without hypertension, who could still benefit from the use of ACE inhibitors or ARBs to prevent microvascular complications. However, the untreated target population in this cohort of MCO patients was less than 2%-20 patients with renal disease but without hypertension and not receiving either an ACE inhibitor or an ARB.
Overall, patient adherence with therapy was generally good as measured by MPR. Adherence to ACE inhibitor or ARB therapy was directly associated with age. A potential concern in these study results was an average delay of approximately 8 days in refilling prescriptions for ACE inhibitors or ARBs in this cohort, for which cost was not a barrier to adherence with therapy since members received their prescriptions at no charge ($0 copayment). Medicaid MCOs may choose to target those patients our study identified as being the most at risk for failing to receive and adhere to ACE inhibitor or ARB therapy-